Midbrain dopamine (DA) neurons mediate drug reward and drug abuse. Addictive drugs such as cocaine, amphetamine, opioids and cannabinoids all activate these neurons and are capable of inducing lasting changes on DA neuron self-regulation with consequent impact on dopaminoceptive targets. Long-term functional modifications within DA neurons are presumed to reflect altered gene expression to drug-induced changes in key transcription factor activities. The proposed research will develop animal models allowing for the DA cell-specific inducible deletion or increased expression of two key transcription factors known to function in midbrain DA neurons;cAMP-response element binding protein (Creb) and signal transducer and activator of transcription-3 (Stat3). The research will then determine the impact of manipulating transcription factor activity in developing or adult mice on the expression of downstream targets of these transcription factors and on the anatomy and gene expression of midbrain dopamine neurons. Recent advances in genetic targeting have allowed for the cell-specific deletion of target genes in specific neuronal cell types. The proposed R21 project will develop mouse models combining BAC recombineering with the Tet-On system to provide for doxycycline (DOX)- inducible deletion or over-expression of Creb or Stat3 specifically in DA neurons. The activity of both transcription factors have been linked to DA neuron function. Creb has been implicated in DA neuron development/survival and DA neuron responses to morphine. Stat3 has been shown to be activated by the metabolic hormone leptin and could mediate the link between metabolic state and the motivation to eat. Global gene expression will be used to determine downstream targets of these transcription factors in DA neurons and DA neuron anatomy and function will be assessed under altered Creb or Stat3 levels induced by DOX during development or adulthood. Dopaminergic pathways in the brain have been a research focus for investigators studying Parkinson's disease and other movement disorders, schizophrenia, mood disorders, and drug addiction. The proposed research will develop mouse models to facilitate understanding of these pathways by allowing for selective gene modifications specifically in these neurons. The models will also allow the modifications to be made early or late in life in order to gauge their impact on the development and maintenance of the dopamine neurons.